The molecular pathogenesis of oral cancer remains poorly understood. A substantial proportion of oral dysplasias and cancers, but not all, are associated with human papillomavirus (HPV) infection. A better understanding of the mechanisms underlying HPV+ and HPV-oral disease incidence and progression is needed to develop new approaches to this highly lethal disease. The focus of this project is on the role of two novel cellular proteins, macrophage inhibitory factor-related protein (MRP)-8 and MRP14 in the pathogenesis of oral cancer. MRP8 and MRP14 are members of the factor-related protein (MRP)-8 and MRP14 in the pathogenesis of oral cancer. MRP8 and MRP14 are members of the S-100 calcium binding protein family. They have been shown to have multiple intracellular and extracellular functions in white blood cells, but their biology in normal and neoplastic oral epithelium has not yet been studied. MRP8 and MRP14 may regulate intracellular calcium levels and play a role in calcium-dependent signaling pathways in both MRP14 may regulate intracellular calcium levels and play a role in calcium-dependent signaling pathways in both HPV+ and HPV-cells. In HPV+ cells, the MRP8/14 may regulate intracellular calcium levels and play a role in calcium-dependent signaling pathways in both HPV+ and HPV- cells. In HPV+ cells, the MRP8/14 complex may inhibit casein kinase II-mediated phosphorylation of the HPV E7 oncoprotein thereby attenuating its function. We have shown that MRP8 and MRPP14 levels vary considerably depending on the stage of oral disease. In normal epithelium, MRP8 and 14 expression are low, but are highly up-regulated in low-grade dysplasia. However, high-grade dysplasia and cancers are associated with loss of expression of MRP8 and/or MRP14. We hypothesize that MRP8 and MRP14 inhibit cell growth through a variety of mechanisms and that up-regulation of MRP8 AND mrp14 represents a cellular response to events initiating low-grade dysplasia, such as HPV infection. We also hypothesize that loss of expression of MRP8 and/or MRP14 represents a step in oral disease progression. Accordingly, we have four specific aims: 1) To analyze expression of MRP8, MRP14 and effect of MRP proteins on HPV+ and HPV-oral epithelial cell lines; 3) To determine the effects of the MRP8/14 complex on the phosphorylation and function of the HPV E7 protein; and 4) To study the effects of the MRP8/14 complex on HPV+ and HPV-oral cancer cell growth in the nude mouse model. This project will advance our understanding of the role of MRP8 AND mrp14 in oral dysplasia and cancer if our hypotheses are confirmed, manipulation of MRP expression in oral dysplasia and cancer may represent a novel therapeutic approach to treatment of these diseases.